The purposes of this study were to (a) explore the relationships among sleep disturbance, depression, and quality of life, and to (b) test whether depression mediates the effect of sleep disturbance on quality of life in patients with hepatocellular carcinoma (HCC). A cross-sectional study was conducted with a total of 73 patients with HCC. All participants completed questionnaires that included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ C-30), the Pittsburgh Sleep Quality Index-Taiwan Form, and the Depression subscale of the Taiwanese version of the Hospital Depression and Anxiety Scale. Path analysis was used to test the mediation role of depression. The major results were as follows. First, sleep disturbance is positively related to depression (r=0.48, p=0.000). In addition, sleep disturbance and depression are negatively interrelated with quality of life (r=-0.310, p=0.008; r=-0.367, p=0.001) in patients with HCC. Moreover, depression completely mediates the effects of sleep disturbance on quality of life. These findings suggest that depression is an important mechanism underlying the relationship between sleep disturbance and quality of life for patients with HCC. In conclusion, this is the first study to explore how the phenomenon of symptoms (sleep disturbance and depression) affects quality of life in patients with HCC and to investigate the mediating role of depression that underlies the relationship between sleep disturbance and quality of life. The current findings could be of clinical importance and imply a need to consider management of sleep disturbance and depression simultaneously.